DE2354389A1 - CHINAZOLINE COMPOUNDS AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

- Qr.-inc. H.

Dü'ing- W. oiockmv "■""\

8 Munich Sa. tfaxirmücnsie. 43

^SA . ■ '· October 30, 1973

P 7442

Eisai Go ", Ltd.

6-10, 4-chome, Koishikawa, Bunkyo-ku, Tokyo, Japan

Quinazoline compounds and process for their preparation

The invention relates to new quinazoline compounds; it relates in particular to new 2- (4- '-substituted ~ homopiperazino) -> 4-amino = 6 _? 7 ~ dimethoxy-quinazoline of the general formula ".

wherein A represents the group

(i) R ¹ -CO-; wherein R ^{1 is} a lower alkyl group having 1 to 4 carbon atoms, a phenyl group substituted by a halogen atom, a methoxy group or a methanesulfonyl group, a tin-substituted or substituted by, eini-Hairögenatom, a methoxy group or a methylene • dioxy group or a styryl group

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Furoyl group means, or

(ii) R -, where R is a Fiedrigalky! group with 1 to 4 carbon atoms, a benzyl group substituted by a halogen atom or a methoxy group, or means a ß-pyridylethyl group,

as well as the pharmacologically acceptable acid addition salts thereof and a process for the preparation of these quinazoline compounds. .

Examples of pharmacologically acceptable acids are inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, fumaric acid, maleic acid, tartaric acid, citric acid, succinic acid and methanesulfonic acid. The compounds of the formula I given above and their pharmacologically acceptable acid addition salts have different pharmacological effects, in particular an excellent hypotensive effect on. '

The compounds of the formula I according to the invention are according to manufactured using the following process:

^CH 3 °

N NH + A-X

(III)

N N-A

409 819/1163

wherein A has the meanings given above and X represents a functional group that is a nitrogen-carbon Bond, i.e. the compounds of the formula I are prepared by reacting 2-homopiperazino-4-amino-6,7-aimethoxy-quinazolines of the general formula II with reactances of the general formula III.

The reactants of the formula III- "are given in the meanings of A and the reactions taking place with it divided into two groups:

(i) if A means the remainder R -CO-:

Z-Homopiperazino - ^ - amino-e ^ -dimethoxy-quinazoline of the general formula

II

are reacted with carboxylic acids of the general formula

R ¹ -COOH-III '

or reactive derivatives thereof. Examples of responsive Derivatives of the acids are acid halides, acid anhydrides and reactive esters. The reactions can in the absence of a solvent or in the presence of a ■ organic reaction solvent inert to the reaction such as benzene, toluene or xylene will. If the reaction is carried out at room temperature, ketonlö smitt el such as acetone or Methyl ethyl ketone, can be used without causing side reactions

4 0 9 8 19/1 1. 6 3

appear. The reaction can be carried out smoother, when using an acid removing agent such as triethylamine Alkali bicarbonate or pyridine used in the reaction system; "."

(ii) if A is the radical R-:

Compounds of the general formula II given above reacted with halides of the general formula

R ² -X III "

wherein X represents a halogen atom. The reactions can be carried out in the absence of a solvent or in the presence of an organic Solvent that is inert to the reaction, e.g. in the presence of lower alcohols such as methanol, Ethanol, propanol or isopropanol, a benzene compound, such as benzene itself, toluene or xylene, an ether such as diethyl ether, diisopropyl ether or tetrahydrofuran carried out will. The reaction temperature can suitably be within the range from room temperature to the boiling point of the solvent used can be selected. The reaction can be carried out more smoothly by using an acid removing agent such as triethylamine in the reaction system. Alkali bicarbonate or pyridine is used.

The compounds of the formula II used as starting materials in the process according to the invention represent new compounds which can be synthesized by the following method:

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Deformylation CH ^ O

The compound of the formula II can be prepared by ■ reaction of 2-chloro-4-amino-e ^ -dimethoxy-quinazoline (IV) with IT-iOrmyl-homop.iperazine (V) and subsequent deformylation of the 2- (li '-J ^l ormyl-homopiperazino) - ⁱ l -amino-6 _i 7-Ä.imethoxy-quinazoline (VI) in a manner known per se. ■ -. "...

The biological activities of the compounds according to the invention, in particular with regard to their effectiveness for lowering blood pressure in hypertension, are illustrated by the pharmacological tests described below. Some of the compounds of the formula I according to the invention have a better biological activity than prazosin (US Patent 3,511,836), which in terms of its chemical formula and its biological activity with the compounds of formula I is comparable.

Below are the chemical formulas of two representative ones Representatives of the compounds according to the invention and the Standard compound prazosin indicated:

Compound_Aj_ 2- [ΓΓ · - (2-Furoyl) -homopiperazino] -4 ~ amino-6,7-dimethoxy-quinazoline hydrochloride . "·

-AO 9 81 9/1 163

Compound__Bj_ 2- (N '-Butyroyl-homopiperazino) -4-amino-6,7-dimethoxy-quinazoline hydrochloride

Prazosinj_ 2- [N '- (2-Furoyl) -piperazino] - ^ - amino-e, 7 ~ dimethoxy-quinazoline hydrochloride.

The invention is explained in more detail below with reference to the accompanying drawings. Figures 1 to 3 of the accompanying drawings have diagrams showing the results of pharmacological tests which were carried out with the two compounds according to the invention and erazosin.

The hypotensive effect was demonstrated by the following animal experiments shown:

Attempt 1

The compounds were dissolved in saline and administered intraperitoneally to normotensive rats (with a normal Blood pressure) administered under sodium pentobarbital anesthesia. Compounds A and B as well as prazosin reduced the Blood pressure by 20 to 40 mm Hg and prevented the hypertensive Effect of adrenaline (3 jug / kg, intravenous) »During regarding the degree of nypotensive effect between the three connections there was no detectable difference, the antiadrenergic effect of compound A was stronger more pronounced than that of compound B and of prazosin.

Attempt 2

Through chronic treatment with deoxycorticosterone acetate and saline, had experimental hypertension induced. At an oral dose of 1 mg / kg of the respective compounds, blood pressure was around 40 to

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60 mm Hg and the hypotensive effect lasted longer
than 6 hours. ·

Attempt 3

The compounds lowered the blood pressure of one through inbreeding generated a strain of spontaneous hypertension (SHR) rat bred by Okamoto and Aoki. the Pig. 1 of the holy drawings explains in a comparative way the hypotensive effect of the respective compounds at an oral dose of 1 mg / kg at SHR. the Compound A was most effective in this model hypertension and the effect of compounds A and B lasted more than 12 Hours on. '■

By some experimental data on their mechanism the hypotensive effect and the general pharmacological properties became the following specific characteristic of compounds A and B explains:

Attempt 4-

The contraction of an isolated vas deferens through hearing
Adrenaline was prevented by treatment with the compound Ä and with the compound B as well as with prazosin. The'
Figures 2 and 3 of the accompanying drawings explain the interaction between horadfenalin and prazosin or
between horadrenaline and compound A. The sigmoid curve of dose (concentration of noradrenaline (in mol / ml)) - responsiveness (contraction of the vas deferens)
was shifted parallel to the right under the influence of prazosin (1 χ 10 to 1 χ ΛΟ Μοί / ml), ie a competitive antagonism between noradrenaline and prazosin was found (FIG. 2). Compound A increased the dose-

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Sensitivity curve of norepinephrine in more pronounced Dimensions as shifted to the right by prazosin. Besides this shift to the right, it was the maximum Contraction by norepinephrine under the influence of the compound A noticeably decreased. This means that the connection A is not only a competing component, but also has a component for the Mcht competition inhibition against the antagonist en (Fig. j5). The interaction between compound B and boradrenaline was as found was, analogously to that with the compound A. In the following table I the 5 °% inhibition concentration ' (IDj-q) of compounds A, B and of prazosin against noradrenaline, i.e. the calculated concentration of the particular compound given which half the contraction of the vas deferens under the influence of foradrenaline (1 χ 10 "~ Mol / ml). The relative According to this, efficacy values for compound A were 10, for compound B: 4 and for prazosin: 1 (Table I).

Table I. 2 (Mol / ml) link 5 χ 10 "" Connection A 2 χ 10 "" ⁸ Connection B χ 10 "' Prazosin Attempt 5

It was found that the compounds A and B had a strong Have an inhibitory effect on platelet aggregation. The aggregation of platelets was made by adding adenosine diphosphate (1 χ 10 mol / ml) to a platelet induced rich plasma prepared from rabbit plasma by centrifugation at 150 g for 20 minutes. the Platelet aggregation was observed in the presence of 1.25 x 10 "

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g / ml of compound A and compound B clearly while unaffected by · prazosin (Table II).

A. Table II Inhibition (%) link Concentration (g / ml) 7th link B. ■ 1.25 x 10 ~ ⁶ 20th 1.25x10 ""? 11 link 1.25 x 10 " ⁶ 23 1.25 xiO " ⁵ 0 Prazosin 1 P 5 ν 10 "" ^
l) <Z? X JU 2 1.25 X 10 ~ ⁵

From the above results, the following became Conclusions drawn:. . .

1.) -The compound A and the compound B were related to their hypotensive effect is equally effective or somewhat more effective than prazosin. It is particularly noteworthy that the hypotensive Effects of compounds A and B in rats with spontaneous hypertension more pronounced and long-lasting were than those of prazosin, because the animals with a congenital hypertension were sometimes more preferable than those of prazosin Model for genuine hypertension.

2.) The results of. Experiment No. 4 with respect to. the interaction with norepinephrine show that the 'compounds A and B differ in terms of the mechanism of action of prazosin can distinguish; Compounds A and B have, in addition to their strong α-blocking effect, a direct one relaxing effect on the smooth muscles.

3.) In addition to the hypofcensive effect, prevent the Compounds A and B are effective in an experimental manner

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evoked platelet aggregation. The aggregation of platelets is one of the factors in their formation of thrombi, which are sometimes the · cause of death in disorders of the coronary and cerebral circulation in connection with a , high-frequency hypertension. Therefore, the inhibiting effect becomes on platelet aggregation as beneficial viewed. Prazosin does not have such an effect or its effect is negligible.

As indicated above, the compounds according to the invention are effective for the prevention and treatment of various types of hypertension, for example genuine, renal and malignant hypertension. The compounds can be administered both orally and parenterally in suitable dosage forms, for example in the form of tablets, pills, granules, capsules ^ powders, solutions and suppositories, can be used. In one moderate or severe hypertension, the recommended for an adult dose may be within the range yon 1 to 200 mg per day, preferably from 1 to mg per Tagjbei oral administration lie.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

example 1

Synthesis of 2- [N ~ (2-furoyl) homopiperazino3-4-amino-6,7- dimethoxy-quinazoline

(a) Synthesis of 2-homopiperazino-4 ~ ainino-6,7-dimethoxy-

£ hinazo_lin _r

17 g of 2-chloro-4-amino-6,7-dimethoxy-quinazoline and 18.2 g N-formyl homopiperazine was added to 170 ml of butanol and the whole was refluxed with stirring for 3 hours. To. Completion of the reaction became the mixture cooled and the precipitated crystals were

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235-389

filtered off, washed with a small amount of ethanol and air dried. 25 g of crude crystals were obtained. 13 g of the "crystals thus obtained" were added with 80 ml of 9% hydrochloric acid. The mixture was refluxed with stirring for 60 minutes. After the completion of the reaction, the mixture was allowed to cool. The crystals thus precipitated became filtered off and then recrystallized from a methanol / ethanol mixture, yield 10.7 g (80.4%) _v F. 24-6 to 247 ^O C. Element ar analysis for C ^, - H ₂ ^ N ₅ 0 ₂ . 2HC1.1 / 2H ₂ 0: _. '■ _, ■ calc .: G 46.74 · H 6.29 N 18.17 . Found: 46.44 6.40 17.90%.

(b) Synthesis of 2- [IP- (2-furoyl) -homopiperazino3-4-amino-

A solution of 3 g of 2-homopiperazino-4-amino-6,7-dimethoxy- quinazoline in 60 ml of acetone became a solution of 1.3 g 2-Eurancarboxylic acid chloride in 30 ml of acetone with stirring and added dropwise with ice cooling. After the addition was complete stirring continued for an additional hour to achieve the Complete the reaction * The crystals precipitated in the process were filtered off and from a methanol / lthano 1 mixture recrystallized, yield 3.1 g (70.4%), mp 278-280 ° C. Elemental analysis for C ^ H ^ xNcO ^ .HCl: calc .: C 55.36 H 5.59 N 16.15 found: 55.30 5.4-5. 16.18% /

Example 2 . .

Synthesis of 2- (N -Butyl-homopiperaz'ino) -4> -amino-6,7- dimethoxy-quinazoline - · - ~ -

2 g of triethylamine were added to a solution of 1.5 S 2 homo- piperazino ^ -amino-ö ^ -dimethoxy-quinazoline and 1.5 g a-Butyl chloride in 20 ml of n-butatiol was added and the mixture was refluxed with stirring for 24 hours.

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~ 12 -

After the completion of the reaction, the solvent was distilled off and then the residue thus obtained became. made alkaline by adding a 10% aqueous sodium hydroxide solution. The oily substance which separated out was extracted with chloroform. The extract was washed with water, over? Potassium carbonate dried and filtered. The filtrate was concentrated. The residue obtained in this way was dissolved in 39 nil isopropanol. 3 ml of saturated isopropanol / hydrochloric acid were added to the solution and the crystals obtained were filtered off and recrystallized from a methanol / ethanol-G mixture. The desired compound was obtained in the form of the dihydrochloride, yield 0.9 g (50.6%). Elemental _{analysis for C ^ QH 29} N ₅ O ₂ .2HCl.1 / 2H ₃ O: calc .: C 51.68 H 7 , 32 N 15.86 found: 51.74- 7.13 16.42%

Examples 5 to 17 .

The various compounds listed in Table III below were prepared using procedures similar to those described in Examples 1 and 2 were applied. The results are summarized in Table III below.

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Table III

!Example

10

CH ₃ CQ-

CHCO-

CH ₃ CB ₂ CH ₂ CO-

CH = CH-CQ-

Molecular formula a \ ( ⁰ C)

^G 17 ^H 23 ^N 5 ^O 3 ' ^HCÄ ' ^H 2 ^O 235-240 ~

- 25 Ö

280-282

235-240

HC £

225-235

^C 23 ^H 27 ^N 5 ° 5 ^{S> HC £}

^C 24 ^H 29 ^N 5 ^Q 5 ' ^{HC £ -1 / 2H} 2 ° 220-225

210

215

set\

51.05 51.16

54.46 54.20

'55 .66 55.40

53.22 53.18

58.27 57.78

52.91 52.98

56.18 5 6,.: 06

59.06 58.65

6.57 6.34

6.99 6.97

6.90 6T89

5.49 5.79

5.97 6.09

5.42 5.44-

6.10 6.29

6.21 5.82

τ% τ

17.52 17.8 "

16.71 17.Iff '

17.09 16.79

14.11 13.61

14.78 14.32

13.42 13.45

13.65 13.4

14.35 14.20

co cn

co

OO

co

example

Molecular formula p. ' (° C)

Elementary analysis

ber.

11

C & - # \ - CH = CH-C0-

^C 24 ^H 26 ^N 5 ^O 5- ^{HC £} ' ^H 2 ° 245-250

55.17
55.62

5.61 5.4 6

13.41 13.83

12th

0 W VCH = CH-CO-

C ₂₅ H ₂₆ N ₅ O ₅ .HCJl. 1 / 2H ₂ O

235-240

57.51
57.80

5.42 5.62

13.42 13.52

O CO OO

13th

CH3O

CH3O -0-CH = CH-CO-

CH ^ O-

C ₂₇ H ₃₁ N ₅ O ₆ • HC £ -1 / 2H ₂ O

292-294

57.18
57.52

5.88 , 6.06

12.35 12.41

CH ₃ -

^C 16 ^H 23 ^N 5 ° 2

208-210

60.54
60.37

7.32 7.22

07/22 07/22

15th

^C 22 ^H 25 ^{C £} 2 ^N 5 ° 2 * ^{2HC £} ~~ 240 - 245

49.35
49.44

5.09 5.56

13.08 12.52

16

C23H29N5O3-2HCA -280-285

55.63
55.59

6.31 6.36

14.11 14.34

17th

250-260

51 ·. 01
50.52

April 6, 6.30

16.23 15.90

Claims (1)

(i) R-CO-, where H. is a lower alkyl group with 1 Ms 4 Carbon atoms, one through a halogen atom, one • Substituted methoxy group or a methanesulfonyl group Pheny! Group, an unsubstituted or by a Halogen atom, a methoxy group or a methylenedioxy group substituted styryl group or a ÜTuroylgruppe means - or. 2 2 ' (ii) Η- »where R is an IT-lower alkyl group with 1 to 4-carbon atoms ^ one through a halogen atom or. a methoxy group substituted benzyl group or means a ß-pyridylethyl group, as well as the pharmaceutically acceptable acid addition salts thereof. ·:. 2 process for the preparation of 2- (4'-substituted-homopiperazino) -4-amine-6,7-dimethoxy-quinazolines the general formula 409 8 19/1163 --16 - 1 1 in which A denotes the group R -CO- in which E is a lower alkyl group having Ί to 4 carbon atoms, a phenyl group substituted by a halogen atom, a methoxy group or a methanesulfonyl group, an unsubstituted one. or by a halogen atom, a methoxy group or a methylenedioxy group substituted styryl group or a furoyl group, characterized in that a 2-homopiperazino-4-amino-6,7-dimethoxy-quinazoline with a Compound of the general formula E -00OH or a reactive one Derivative thereof. 3. Process for the preparation of 2- (4 -'- substituted-Homopipera-. zino) -4-amino-6,7-dimethoxy-quinazolines of the general formula ο · where R is a lower alkyl group having 1 to 4 carbon atoms, a benzyl group substituted by a halogen atom or a methoxy group or a β-pyridylethyl group, characterized in that a 2-homopiperazino-4-amino-6,7-dimethoxy group is used. quinazoline with a compound of the general
means. general formula El converts, in which X is a halogen atom 09819/1163 Blank page